title: Neurotransmitter transporters in schistosomes: structure, function and prospects for drug discovery.
abstract: Neurotransmitter transporters (NTTs) play a fundamental role in the control of neurotransmitter signaling and homeostasis. Sodium symporters of the plasma membrane mediate the cellular uptake of neurotransmitter from the synaptic cleft, whereas proton-driven vesicular transporters sequester the neurotransmitter into synaptic vesicles for subsequent release. Together these transporters control how much transmitter is released and how long it remains in the synaptic cleft, thereby regulating the intensity and duration of signaling. NTTs have been the subject of much research in mammals and there is growing interest in their activities among invertebrates as well. In this review we will focus our attention on NTTs of the parasitic flatworm Schistosoma mansoni. Bloodflukes of the genus Schistosoma are the causative agents of human schistosomiasis, a devastating disease that afflicts over 200 million people worldwide. Schistosomes have a well-developed nervous system and a rich diversity of neurotransmitters, including many of the small-molecule ("classical") neurotransmitters that normally employ NTTs in their mechanism of signaling. Recent advances in schistosome genomics have unveiled numerous NTTs in this parasite, some of which have now been cloned and characterized in vitro. Moreover new genetic and pharmacological evidence suggests that NTTs are required for proper control of neuromuscular signaling and movement of the worm. Among these carriers are proteins that have been successfully targeted for drug discovery in other organisms, in particular sodium symporters for biogenic amine neurotransmitters such as serotonin and dopamine. Our goal in this chapter is to review the current status of research on schistosome NTTs, with emphasis on biogenic amine sodium symporters, and to evaluate their potential for anti-schistosomal drug targeting. Through this discussion we hope to draw attention to this important superfamily of parasite proteins and to identify new directions for future research.
authors.affiliation: Institute of Parasitology, McGill University, Macdonald Campus, 21, 111 Lakeshore Road, Ste. Anne de Bellevue, Quebec H9X 3V9, Canada. Electronic address: paula.ribeiro@mcgill.ca.
authors.forename: Paula
authors.initials: P
authors.lastname: Ribeiro
authors.forename: Nicholas
authors.initials: N
authors.lastname: Patocka
mesh_terms: D000818:Animals; D001679:Biogenic Amines / Q000378:metabolism*; D016000:Cluster Analysis; D050483:Dopamine Plasma Membrane Transport Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism; D055808:Drug Discovery; D023281:Genomics; D015801:Helminth Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D018377:Neurotransmitter Agents / Q000378:metabolism*; D050479:Neurotransmitter Transport Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012550:Schistosoma mansoni / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012555:Schistosomiasis mansoni / Q000188:drug therapy / Q000469:parasitology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001679:Biogenic Amines; D050483:Dopamine Plasma Membrane Transport Proteins; D015801:Helminth Proteins; D018377:Neurotransmitter Agents; D050479:Neurotransmitter Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins
keywords: Biogenic amines; CNS; DAT; Dopamine transporter (DAT); GABA; GAT; GLT; Helminth; NAT; NTT; Neurotransmitter; Neurotransmitter transporter (NTT); OAT; PZQ; RNA interference; RNA interference (RNAi); RNAi; SERT; SLC; SSRI; Schistosoma; Serotonin transporter (SERT); VMAT; central nervous system; dopamine transporter; gamma-aminobutyric acid; gamma-aminobutyric acid (GABA) transporter; glutamate transporter; iDAT; invertebrate dopamine transporter; neurotransmitter transporter; noradrenaline transporter; octopamine/tyramine transporter; praziquantel; selective serotonin reuptake inhibitor; serotonin transporter; short interfering RNA; siRNA; solute carrier; vesicular monoamine transporter